Powdery pharmaceutical compositions for inhalation

ABSTRACT

Powdery pharmaceutical compositions including an active ingredient and carrier particles containing only a small amount of lubricant, 0.05-0.5% by weight, are used to prepare dry powder inhalers in order to increase the fine particle dose. A process for coating the surface of the carrier particles with such little amount of lubricant is also provided. Use of limited amount of lubricant is safe and provides ordered stable mixtures without segregation of the active particles during handling and before use.

This invention relates to improved powdery pharmaceutical compositionsfor use in dry powder inhalers. The improvement is concerned withmechanical stability, performances and safety.

Inhalation anti-asthmatics are widely used in the treatment ofreversible airway obstruction, inflammation and hyperresponsiveness.

Presently, the most widely used systems for inhalation therapy are thepressurised metered dose inhalers (MDIs). which use a propellant toexpel droplets containing the pharmaceutical product to the respiratory.tract.

However, despite their practicality and popularity, MDIs have somedisadvantages:

-   i) the majority of the dose released deposits in the oropharynx by    impaction and only a small percentage penetrates directly into the    lower lungs;-   ii) the already small proportion of drug which penetrates the    bronchial tree may be further reduced by poor inhalation technique;-   iii) last but not least, chlorofluorocarbons (CFCs), such as freons    contained as propellants in MDIs, are disadvantageous on    environmental grounds as they have a proven damaging effect on the    atmosphenic ozone layer.

Dry powder inhalers (DPIs) constitute a valid alternative to MDIs forthe administration of drugs to airways. The main advantages of DPIs are:

-   i) being breath-actuated delivery systems, they do not require    co-ordination of actuation since release of the drug is dependent on    the patient own inhalation;-   ii) they do not contain propellants acting as environmental hazards;-   iii) the quantity deposited by impaction in the oropharynx is lower.

DPIs can be divided into two basic types:

-   i) single dose inhalers, for the administration of single subdivided    doses of the active compound;-   ii) multidose dry powder inhalers (MDPIs), pre-loaded with    quantities of active principles sufficient for longer treatment    cycles.

MDPIs are considered more convenient to the patient than single doseDPIs, not only because they provide a number of doses sufficient for.longer treatment cycles but also because of their ease of use andunobtrusiveness.

Dry powder dosage forms are generally formulated by mixing the cohesivemicronised drug with coarse carrier particles, giving rise to orderedmixture where the micronised active particles adhere to the surface ofthe carrier particles whilst in the inhaler device.

The carrier material, most commonly lactose, makes the micronised powderless cohesive and improves its flowability, making easier handling thepowder during the manufacturing process (pouring, filling etc.). Duringinhalation, the small drug particles separate from the surface ofcarrier particles and penetrates into the lower lungs, while the largercarrier particles are mostly deposited in the oropharyngeal cavity.

The redispersion of drug particles from the carrier surface is regardedas the most critical factor which governs the availability of themedicament to the lungs. This will depend on the mechanical stability ofthe powder mix and the way this is influenced by the adhesioncharacteristics between the drug and the carrier and the external forcesrequired to break up the non covalent bonds formed between adheringparticles. Too strong bonds between adhering particles may preventindeed the separation of the micronised drug particles from the surfaceof carrier particles. ID particular, the efficiency of the redispersionprocess is strictly dependent on the carrier surface properties, theactual particle size of both the drug and the carrier and the drug tocarrier ratio. Consequently, different approaches aimed at modulatingone or more of these parameters have been proposed to promote therelease of the drug particles from the carrier particles and, hence, toincrease the percentage of the respirable fraction. In the prior art,the use of a ternary component, with lubricant or anti-adherentproperties, has been also suggested as a solution of the technicalproblem.

Fisons patents GB 1242211 and GB 1381872 described powders forinhalation obtained by simple mixing of a medicament with a particlesize of less than 10 microns and a coarse carrier whose particle sizefalls in a well defined range. They also disclosed that it may be usefulto coat the surfaces of the particles and/or carrier withpharmaceutically acceptable material, such as stearic acid or polymersfor giving a sustained release action to the medicament.

Chiesi WO A 87 05213 described a carrier, comprising a conglomerate of asolid water-soluble carrier and a lubricant, preferably 1% magnesiumstearate, for improving the technological properties of the powder insuch a way as to remedy to the reproducibility problems encounteredafter the repeated use of the inhaler device.

Staniforth et al. (J. Pharm. Pharmacol. 34, 141-145, 1982) observed thatmagnesium stearate is able to modify the adhesion of salicylic acid tosucrose but, the amount used (0.5-4.0%) destabilises the mixture to theextent that significant segregation occurs.

Kassem (London University Thesis, 1990) studied the effect of 1.5% w/wmagnesium stearate or Aerosil 200 (trade name for colloidal silicondioxide) on the de-aggregation of powders made of salbutamol sulphateand lactose. Although the ‘respirable’ fraction increased when magnesiumstearate was added, the reported amount is too great and reduces themechanical stability of the mixture before use. Furthermore, beingmagnesium stearate poorly water-soluble, its presence in such amount mayrise some concerns as to a potential irritation or toxicity of thisexcipient, part of which can be inhaled by the patient together with theactive ingredient. According to Staniforth (WO 96/23485), the reporteddrawbacks can be solved by adding physiologicallyacceptable/water-soluble additives with anti-adherent properties whichdo not make segregation of the active particles from the surfaces of thecarrier particles during manufacturing of the dry powder and in thedelivery device before use. In the said document, the anti-adherentmaterial, preferably 1-2% leucine in particulate form, promote therelease of the active particles by saturating the high energy sites ofthe carrier particles. Although it is generically disclosed thatmagnesium stearate, being highly surface active, should be added inparticularly small amounts', the use of such excipient is considered notadvisable.

It has now been discovered, and this is an object of the presentinvention, that lubricants like magnesium stearate can be advantageouslyand safely used as excipient for powdery pharmaceutical composition insuch amount by weight based on the total weight of the powder of lessthan 0.5%; for steroids, the optimum amount of additive turned out to be0.25%, whereas, for salbutamol base, it turned out to be 0.10%. Contraryto the teaching of the prior art (Peart et al. Pharm. Res. 14, S 142,1997), 0.1% of magnesium stearate is sufficient for increasing in asignificant way the fine particle dose, when salbutamol base instead ofsulphate is used.

The invention also provides a method for producing a homogeneous carrierfor powders for inhalation independently on the scale of mixing, themethod including a step for coating the most as possible surface of thecarrier particles with a little amount of lubricant. We have indeedfound that it is advantageous to attain the highest as possible degreeof coating of the carrier particles surface with the lubricant toincrease the release of the active particles and, hence, the‘respirable’ fraction. In the prior art, it was already known that thefilm forming properties of lubricants depend on the mixing time andsignificantly affect the compressibility characteristics of powders fortablets, but an advantageous relationship between the degree of coatingand the ‘respirable’ fraction has never been reported before. We havealso found, and this is another aspect of the invention, that use oflubricants in such little amount for coating the carrier, is sufficientfor improving the flowability of the powder without causing mechanicalstability problems of the mixture before use.

Finally we have found that the introduction of magnesium stearate insuch a small amount is safe and does not produce any toxicologicallyrelevant effect after repeated administration.

Advantageously the carrier of the invention is prepared by mixing thecarrier particles and the lubricant particles for at least 2 min in amixer in such a way as that no significant change in the particle sizeof the carrier particle occurs. Preferably, the carrier is mixed for atleast 30 min using a rotating body mixer with a rotating speed between5-100 r.p.m. or a stationary body mixer with a rotating mixing blade ora high-speed mixer. More preferably, the carrier is mixed for al leasttwo hours in a Turbula mixer at 16 r.p.m.

Advantageously, the carrier particles and the lubricant particles aremixed until the degree of molecular surface coating is more than 10% asdetermined by water contact angle measurement. Preferably, carrierparticles and lubricant particles made of magnesium stearate are mixeduntil the water contact angle of the ‘coated’ carrier particles is morethan 36° corresponding to more than 10% degree of molecular surfacecoating; more preferably, the water contact angle should be more than50° corresponding to more than 23% degree of molecular surface coating.

The carrier particles may be composed of any pharmacologically inertmaterial or combinations of material acceptable for inhalation.Advantageously, the carrier particles are composed on one or morecrystalline sugars. Preferably, the carrier particles are particles ofα-lactose monaohydrate.

Advantageously, all the carrier particles have a particle size in therange 20-1000 μm, more preferably in the range 90-150 μm.

The preferred lubricant is any type of magnesium stearate which may becrystalline or amorphous; its use is described in the embodiments of theinvention by way of examples which do not limit it in any way.

Other lubricants, such as stearic acid, sodium lauryl sulphate, sodiumstearyl fumarate, stearyl alcohol, sucrose monopalmitate and sodiumbenzoate, could turn out to be suitable depending on the type of carrierand drug used.

Advantageously, at least 50% by weight of the lubricant particles have aparticle size more than 4 μm. Preferably, at least 60% of the lubricantparticles made of magnesium stearate have a particle size more than 5μm, with a specific surface area in the range 0.5-2.5 m²/g measured byMalvern.

The ratio between the carrier and the drug are mixed will depend on thetype of inhaler device used and the required dose.

Advantageously, the at least 90% of the particles of the drug have aparticle size less than 10 μm, preferably less than 6 μm.

Drugs include those products which are usually administered byinhalation for the treatment of respiratory diseases, i.e. β-agonists,like salbutamol, formoterol, salmeterol, terbutaline and their salts,steroids like beclometasone dipropionate, flunisolide, budesonide,others like ipratropium bromide.

In a general aspect, the invention also provides a powderypharmaceutical composition for use in a dry powder inhaler, the powderincluding active particles and a carrier where the surface of thecarrier particles carrying the active particles is partially coated witha film of lubricant.

EXAMPLE 1

Determination of the Suitable Amount of Magnesium Stearate to be Addedin beclomethasone-17,21-dipropionate (BDP) Powders for Inhalation

Samples of the carrier were prepared by mixing of α-lactose monohydrate(Meggle D 30) fraction 90-150 μm with 0.1%, 0.25% or 0.5% magnesiumstearate for several hours in a Turbula mixer. Powders mixtures withdifferent BDP concentrations (100, 200 and 400 μg/dose) were prepared bymixing of the carrier and the active ingredient for 30 min in a Turbulamixer at 32 r.p.m.

Multidose devices (Pulvinal®) filled with the mixtures were then testedby using a twin-stage impinger (TSI), Apparatus A (BP 93, Appendix XVIIC, A194). The fine particle dose is calculated as a percentage of thetotal amount of drug delivered from the device (stage 1+stage 2), thatreaches stage 2 of TSI. The results are summarised in Tables 1, 2 and 3(standard deviations S.D., given in parentheses).

No significant increase in fine particle dose is obtained fromincreasing the concentration of magnesium stearate above 0.25%. TABLE 1Formulation Mg Shot Fine particle (100 stearate weight Stage 2 Delivereddose* μg/dose) (%) (mg) (μg) dose (μg) (BDP %) BDP 1 0.10 26.7 (0.3)22.5 (3.5) 99.7 (0.6) 21.9 (2.8) BDP 2 0.25 26.8 (0.1) 33.0 (5.6) 95.3(0.6) 34.5 (6.2)

TABLE 2 Fine Formulation Mg Shot particle (200 stearate weight Stage 2Delivered dose* μg/dose) (%) (mg) (μg) dose (μg) (BDP %) BDP 1 0 24.8(0.4) 14.2 (5.7)  192 (14.0)  7.3 (2.6) BDP 2 0.10 26.6 (0.4) 20.3 (4.6)215 (2.3)  9.5 (2.2) BDP 3 0.25 26.8 (0.6) 48.0 (8.5) 192 (7.8) 25.0(3.7) BDP 4 0.50 26.7 (0.2) 32.3 (2.3) 193 (4.6) 16.7 (1.0)

TABLE 3 Formulation Mg Shot Fine particle (400 stearate weight Stage 2Delivered dose* μg/dose) (%) (mg) (μg) dose (μg) (BDP %) BDP 1 0 — — 355(22.8)  7.3 (0.4) BDP 2 0.10 25.4 (0.3) 100 (11.0) 351 (4.5)  28.7 (3.4)BDP 3 0.25 25.1 (0.4) 142 (22.1) 375 (9.3)  37.9 (5.7) BDP 4 0.50 25.5(0.3)  98 (44.7) 421 (18.4)  23.2 (10.3)

EXAMPLE 2

Determination of the Suitable Amount of Magnesium Stearate to be Addedin Salbutamol Base Powders for Inhalation

Samples of the carrier were prepared as reported in Example 1.

Powder mixtures containing 200 μg/dose of micronised salbutamol basewere prepared by mixing of the carrier and the active ingredient for 30min in a Turbula mixer at 32 r.p.m.

The powder mixtures were filled into inhalers and tested as reported inExample 1.

The results are summarised in Table 4.

0.1% Magnesium stearate is sufficient for increasing in a significantway (t=10.47, p<0.001) the fine particle dose, when salbutamol baseinstead of sulphate is used; no increase is obtained from increasing theconcentration of magnesium stearate above this percentage. TABLE 4 Fineparticle Formulation Mg Shot dose* (200 stearate weight Stage 2Delivered (Salbutamol μg/dose) (%) (mg) (μg) dose (μg) %) SALB 1 0 22.4(0.4) 62.7 (5.3) 185 (5.1) 33.6 (2.9) SALB 2 0.1 26.8 (0.5) 71.3 (3.1)171 (5.0) 41.8 (0.9) SALB 3 0.25 26.9 (0.2) 71.7 (6.1) 171 (1.7)41.6.(3.2) SALB 4 0.5 26.5 (0.5) 68.7 (6.4) 172 (6.0) 39.9 (3.5)

EXAMPLE 3

Determination of the Suitable Amount of Magnesium Stearate to be Addedin Budesonide Powders for Inhalation

A sample of the carrier was prepared by mixing of α-lactose monohydrate(Meggle D 30) fraction 90-150 μm with 0.25% magnesium stearate for twohours in Turbula-T100 mixer at 16 r.p.m.

Powder mixtures containing 100 μg/dose of micronised budesonide wereprepared by mixing of the carrier and the active ingredient for 30 minin a Turbula mixer at 32 r.p.m.

The powder mixtures were filled into inhalers and tested as reported inExample 1.

The results are summarised in Table 5.

0.25% Magnesium stearate significantly increases the fine particle doseof budesonide (t=8.8, p<0.001); TABLE 5 Formulation Mg Shot Fineparticle (100 stearate weight Stage 2 Delivered dose* μg/dose) (%) (mg)(μg) dose (μg) (Budesonide %) BUD 1 0 22.0 — 80.0 21.4 (4.7) BUD 2 0.2521.5 — 79.3 33.6 (2.6)*Average values obtained from three inhalers by actuating 5 shots fromeach inhaler.

EXAMPLE 4

Preparation of the Carrier—Study of the Mixing Conditions

40.528 kg (99.75% w/w) of α-Lactose monohydrate fraction 90-150 μm and0.102 kg (0.25% w/w) of magnesium stearate were mixed in a Turbula mixerT 100 at 16 r.p.m. for several hours. At different mixing times sampleswere withdrawn and tested for uniformity of distribution of magnesiumstearate, particle size, water contact angle and degree of molecularsurface coating calculated according to Cassie et al. (Transactions ofthe Faraday Society 40; 546, 1944). To validate the process, threebatches (40 kg) of the carrier were prepared.

The results are reported in Tables 6 and 7, respectively.

A uniform distribution of magnesium stearate was already achieved at 60minutes blending time (mean value, {overscore (x)}, and coefficient ofvariation, CV %, are given); no significant change in the particle sizewas observed after both Malvern light-scattering and Alpine sievinganalyses. By increasing the mixing time, an increase of the degree ofcoating occurs.

The three different batches give comparable results. TABLE 6 Particlesize Particle size Mg stearate Water contact Degree of Time AlpineMalvern uniformity angle coating min % <80μ % <90μ % <80μ % 90μ x % CV %degree % 10′ — — — — — — 34 15 20′ — — — — — — 36 17 30′ 1.5 4.8 0.9 2.70.228 6.8 36 17 60′ 0.3 2.8 0.9 2.6 0.235 6.1 36 17 90′ 0.6 3.8 1.0 2.90.244 3.7 37 18 120′ 0.7 3.4 0.9 2.7 0.239 7.2 39 20 180′ 0.8 4.2 0.82.6 0.246 2.9 46 29 240′ 1.4 6.3 0.8 2.6 — — 48 32 300′ 0.7 6.6 0.9 2.6— — 50 34 360′ 0.7 7.0 1.0 2.8 — — 51 36 420′ 0.9 7.0 0.9 2.8 — — 51 36480′ 0.8 7.5 0.8 2.6 — — 51 36α-Lactose monohydrate water contact angle 12°Magnesium stearate water contact angle 118°

TABLE 7 Magnesium Particle size Particle size stearate WaterDistribution distribution content contact Mixing (Alpine) (Malvern)uniformity angle Time % <80 μm % <90 μm % <80 μm % <90 μm x (%) CV (%)(degree) CARRIER 1 10 min 34 20 min 37 30 min 1.5 4.8 0.9 2.7 0.228 6.836 60 min 0.3 2.8 0.9 2.6 0.235 6.1 36 90 min 0.6 3.8 1.0 2.9 0.244 3.737 120 min  0.7 3.4 0.9 2.7 0.239 7.2 39 CARRIER 2 10 min 32 20 min 3630 min 38 60 min 0.9 7.2 1.0 3.1 0.196 9.6 38 90 min 40 120 min  1.5 8.11.1 3.3 0.231 10.4 42 CARRIER 3 10 min 32 20 min 31 30 min 33 60 min 0.86.9 2.0 4.5 0.237 7.3 38 90 min 42 120 min  0.8 7.3 1.8 4.2 0.229 3.8 42

EXAMPLE 6

Relationship Between Different Mixing Time of the Carrier and DeliveredFine Particle Dose

40.528 kg (99.75% w/w) of a-Lactose monohydrate fraction 90-150. μm and0.102 kg (0.25% w/w) of magnesium stearate were mixed for several hoursin Turbula T100 mixer at 16 r.p.m. At different mixing times, 2 kgsamples were withdrawn and micronised BDP was added to each sample sothat the nominal weight delivered by Pulvinale inhaler contained 200 μgBDP. The powder mixtures were filled into inhalers and tested asreported in Example 1.

The results are reported in Table 8.

By increasing the mixing time, a significant increase at 420 min of thefine particle dose occurs (t=5.2, p<0.001). TABLE 8 Formulation (BDP 200μg/dose) BDP 1 BDP 2 BDP 3 Mixing time (min) 60 120 420 Shot weight (mg)27.8 (0.6) 28.1 (0.7) 28.2 (0.5) Fine particle dose* (%) 34.1 (8.1) 37.4(4.7) 49.5 (7.8) Stage 2 (μg)  63.1 (12.0) 63.5 (8.1) 102.6 (17.1)Delivered dose (μg) 188.4 (21.1) 169.7 (7.1)  207.2 (9.0) *Average values obtained from three inhalers by actuating 5 shots fromeach inhaler

EXAMPLE 7

Preparation of the Carrier—Comoarison Between Different Mixers

40.528 kg (99.75% w/w) of α-Lactose monohydrate fraction 90-150 μm and0.102 kg (0.25 % w/w) of magnesium stearate were mixed in a sigma-blademixer for 30 min (water contact angle of 53° corresponding to 26% ofmolecularcoating)

Powder mixtures containing 200 μg/dose of micronised BDP were preparedby mixing of the carrier and the active ingredient for 30 min in aTurbula mixer at 32 r.p.m.

The powder mixtures were filled into inhalers and tested as reported inExample 1.

The results are surniarised in Table 9.

No significant difference was observed in the fine particle dose withrespect to the powder obtained with the carrier prepared by using aTurbula mixer at 16 r.p.m. for 2 hours. TABLE 9 Fine particleFormulation Shot Stage 2 Delivered dose (200 μg/dose) weight (mg) (μg)dose (μg) (BDP %) Turbula mixer 25.7 (2.8) 96.2 (7.6) 167.5 (5.7) 57.4(4.3) Sigma-blade 26.6 (2.3) 106.2 (11.2) 192.1 (7.0) 55.2 (6.0) mixer

EXAMPLE 8

Segregation Tendency of BDP Bulk Powder Formulation Containing 0.25%Magnesium Stearate

Composition of BDP Pulvinal® (100, 200 and 400 μg/dose): Strength(μg/dose) Ingredient (mg) 100 200 400 BDP 0.100 0.200 0.400 α-Lactosemonohydrate 25.832 25.735 25.536 Magnesium stearate 0.067 0.064 0.064

The tendency of the powder to segregate was assessed according toStaniforth et al. J. (Pharm. Pharmacol. 34, 700-706, 1982).

Approximately 15 g of powder was filled into a small plastic cylinder,80 mm long and 12 mm in diameter, closed at one end and which could besplit along its axis. This allowed the characterisation of both BDP andmagnesium stearate on the same level in the same bulk mixture. The tubewas mounted in a vibrator (Derrinton VP4) and vibrated at 50 Hz at aforce of 2 g for ten minutes. The tube was then placed in a horizontalposition, divided and 15 samples, each of about 50 mg accuratelyweighed, taken from along its length. The samples were analysed for BDPby HPLC and for magnesium stearate by atomic absorption. The experimentswere carried out in duplicate. The results are reported in Tables 10 and11.

Typical values in coefficient of variation (CV) of BDP samples drawnfrom, a mix judged to be satisfactory are ≦5.0%. After the imposition ofan enhanced gravitational stress, BDP samples show a CV which variesfrom 2.7% and 7.8%. Despite the intense vibration, these variations havenot increased significantly and are consistent with good inhalerperformance when judged in terms of dose uniformity. Samples taken fromthe top of the bed are very similar to the bottom samples.

In the case of magnesium stearate, variability between samples wassomewhat greater than for BDP due to its lower concentration. However,no consistent change in the uniformity of distribution occurred aftervibration and, as with BDP, the content of samples drawn from the top ofthe bed were not different to those drawn from the bottom. It can beconcluded that the ordered mix is very stable and no segregation of BDPand magnesium stearate occurs. TABLE 10 DRUG ASSAY (μg/mg) BDP BDP BDP400 μg/dose 200 μg/dose 100 μg/dose SAMPLE 1 2 1 2 1 2 Top of Cylinder 117.9 17.3 8.6 8.5 4.4 4.4 2 20.5 17.1 7.5 7.6 3.5 3.5 3 16.9 17.6 7.77.7 3.7 3.9 4 18.0 16.9 7.7 7.8 3.8 3.9 5 17.0 17.0 7.5 9.0 4.1 4.2 617.2 17.1 7.6 7.8 3.9 3.8 7 17.4 17.6 7.4 8.1 3.7 3.8 8 17.2 17.1 7.67.7 4.2 3.8 9 16.8 17.3 7.7 7.6 4.5 3.9 10  16.9 16.5 8.3 8.0 3.6 3.811  16.9 18.9 7.8 8.0 4.4 4.0 12  21.1 18.1 7.9 7.9 3.9 3.9 13  17.317.5 7.8 7.3 3.9 4.2 14  19.4 17.1 7.7 7.7 4.2 4.1 15  18.0 19.1 7.8 8.04.4 3.9 Bottom of Cylinder Mean 17.9 17.5 7.8 7.9 4.0 3.9 SD 1.4 0.8 0.20.4 0.3 0.2 CV(%) 7.6 4.3 2.7 5.0 7.8 4.7

TABLE 11 MAGNESIUM ASSAY (μg/mg) BDP 400 μg/dose BDP 200 μg/dose BDP 100μg/dose SAMPLE 1 2 UN-VIBRATED 1 2 UN-VIBRATED 1 2 UN-VIBRATED Top ofcylinder 1 0.115 0.124 0.101 0.101 0.092 0.125 0.082 0.076 0.103 2 0.1160.122 0.103 0.105 0.091 0.121 0.105 0.073 0.150 3 0.114 0.123 0.1070.108 0.093 0.125 0.096 0.091 0.104 4 0.113 0.119 0.109 0.100 0.0930.118 0.107 0.085 0.101 5 0.114 0.126 0.110 0.115 0.089 0.135 0.0940.083 0.110 6 0.108 0.108 0.107 0.103 0.100 0.208 0.098 0.080 0.109 70.111 0.113 0.110 0.111 0.096 0.107 0.104 0.114 0.109 8 0.118 0.1080.108 0.107 0.096 0.101 0.102 0.076 0.102 9 0.107 0.104 0.106 0.1060.094 0.102 0.099 0.082 0.103 10  0.113 0.119 0.107 0.094 0.097 0.1010.104 0.081 0.109 11  0.114 0.120 0.109 0.091 0.094 0.096 0.090 0.0860.105 12  0.116 0.117 0.105 0.083 0.093 0.098 0.100 0.084 0.107 13 0.112 0.101 0.103 0.114 0.077 0.100 0.092 0.079 0.104 14  0.115 0.1040.107 0.081 0.095 0.097 0.091 0.072 0.107 15  0.106 0.097 0.102 0.0800.076 0.100 0.086 0.085 0.105 Bottom of Cylinder Mean 0.113 0.114 0.1060.100 0.092 0.116 0.097 0.083 0.109 SD 0.003 0.009 0.003 0.012 0.0070.028 0.007 0.010 0.012 (CV %) 3.1 8.2 2.7 11.6 7.3 24.6 7.6 12.0 10.9

EXAMPLE 9

Fine Particle Delivery of Magnesium Stearate

A batch of BDP 400 μg/shot powder was prepared by mixing of the drug andthe carrier (lactose/magnesium stearate 99.75/0.25% w/w) under theconditions reported in Example 1. Devices were filled with the mixtureand the fine particle delivery of magnesium stearate was determinedusing a TSI apparatus. The results are reported in Table 12. TABLE 12Total Mg Total Shot weight stearate Mg stearate Mg stearate stage 2 (mg)(%) (μg) (μg) Mean 26.4 0.259 68 19 S.D. 0.31 0.017 4.18 2.39 CV % 1.186.52 6.13 12.5

Considering the low concentration of magnesium stearate in theformulation and the quantity found in stage 2 of TSI, the amount to berespirable will be very low.

This amount has been demonstrated to be safe after toxicity studies indog.

Furthermore, acute and long term tolerance trials were carried out toevaluate toxicity of magnesium stearate in humans.

In the former, 18 healthy volunteers, included in a double blindrandomised controlled cross-over design study, received a single dosecontaining 25.72 mg of lactose and 0.065 mg of magnesium stearate viaPulvinal® inhaler. The introduction of 0.25% magnesium stearate inpowdery pharmaceutical formulation resulted to be safe.

In the long term randomised, controlled, parallel group study, thesafety of magnesium stearate as a carrier was compared to that oflactose. 28 Mild asthmatic patients were treated for 3 months with 400μg BDP b.i.d. delivered either with Pulvinal®, containing 0.065 mg ofmagnesium stearate per dose, or another commercially available DPI,containing 25.536 mg of lactose per dose. Bronchial biopsies andbroncho-alveolar lavages performed at the beginning and at the end oftrial did not evidence accumulation of magnesium in bronchi or inalveolar cells either in Pulvinal® or control group.

1-26. (canceled)
 27. A powder composition comprising active ingredientparticles and carrier particles, the carrier comprising one or morecrystalline sugars coated with a lubricant wherein said lubricantcomprises magnesium stearate in an amount between 0.1 and 0.5 percent byweight of the composition.
 28. A powder according to claim 27 whereinthe crystalline sugar is made of α-lactose monohydrate.
 29. A powdercomposition according to claim 27 wherein the carrier particles have asize within the range 90 and 150 μm.
 30. A powder composition accordingto claim 27 wherein the active ingredient particles have a particle sizeless than 6 μm.
 31. A powder composition according to claim 27 whereinthe active ingredient particles include a steroid.
 32. A powdercomposition according to claim 31 wherein the steroid is selected fromthe group consisting of beclometasone dipropionate, budesonide and itsepimers and flunisolide.
 33. A powder composition according to claim 27wherein the active ingredient includes a β₂-agonist.
 34. A powdercomposition according to claim 33, wherein the β₂-agonist is selectedfrom the group consisting of salbutamol base, formoterol, salmeterol,terbutaline and the salts thereof.
 35. A powder composition according toclaim 27 wherein the carrier particles have a size within the range 20and 1000 μm.
 36. A powder composition according to claim 27 wherein thecarrier consists of said one or more crystalline sugars coated with saidlubricant.
 37. A powder composition according to claim 27 wherein saidlubricant consists of said magnesium stearate.
 38. A powder compositionaccording to claim 36 wherein said lubricant consists of said magnesiumstearate.
 39. A dry powder inhaler containing the powder compositionaccording to claim 27 therein.
 40. A method of treating the lungs in apatient in need thereof comprising administering an effective amount ofthe powder composition according to claim 27 to said patient.
 41. Themethod according to claim 40, wherein the patient is treated for asthma.